To understand the mechanism by which diabetes elevates the risk of cardiovascular disease, specifically peripheral artery disease (PAD), and to investigate new avenues for PAD prevention and treatment. Relevance: Type II diabetes has surged in prevalence by 23% over the last decade and now affects 5% of Americans and 25% of Americans above age 65. Diabetes roughly doubles the risk of myocardial infarction, stroke, and congestive heart failure, and quadruples the risk of PAD. PAD is a debilitating condition of progressive atherosclerotic narrowing of the peripheral arteries. The most common manifestation of PAD is pain with exercise due to occlusion of blood flow to the limbs; severe cases of PAD can also lead to ischemic ulceration, gangrene, and limb amputation. Despite the frequency and severity of diabetes and PAD, the mechanisms linking these conditions remain unclear. The proposed project is consistent with NHLBI's mission to understand the mechanisms leading to cardiovascular disease, specifically PAD, and to investigate potential areas of interest for prevention and treatment. Specific Aims: To (I) evaluate the associations between a range of glycemic phenotypes and circulating levels of fibrosis-related biomarkers in older adults; and (II) determine the role of fibrosis in subclinical and clinical PAD - a complication of diabetes that has not previously been evaluated with respect to fibrosis. For both aims, specific emphasis will be placed on correlating biomarkers with disease pathogenesis. Methods: All studies will be performed using the Cardiovascular Health Study, a unique and richly characterized prospective cohort of 5,888 men and women aged 65 and older. Methods will include cross- sectional, multivariate linear regression and time-to-event analysis using a Cox proportional hazards model, as detailed in the research strategy section. Research Training Program: The program includes individualized and supervised research, coursework, scientific writing, and oral presentations that will prepare Isha Agarwal to build a successful career as a physician-scientist. The project will be co-sponsored by two experienced investigators with complementary skill sets in epidemiology and medicine and demonstrated commitment to mentorship. Additional mentorship will be provided by a senior biostatistician collaborator and a basic science consultant. Implication: This research will be critical in determining which glycemic phenotypes are associated with increased risk of fibrosis, whether easily measured biomarkers of fibrosis can predict the risk of PAD among individuals with impaired glucose regulation, and whether fibrosis represents a potential area of interest for PAD prevention and treatment amid the 21st century epidemics of obesity, glucose intolerance, and diabetes.